Multiple Sclerosis (MS), an inflammatory demyelinating disease, lacks effective treatment because the current MS drugs targeting immunosuppression provide limited, if any, benefit to the central nervous system (CNS) disease where it continues to progress. This proposal is designed to investigate the potential of drugs targeting the Rho family GTPases (RFGs) for induction of endogenous myelin repair mechanisms in the CNS of EAE/MS. Previous studies from our laboratory and others have demonstrated that isoprenoids mediated regulation of RFGs with statins provides immunomodulatory and blood-brain-barrier protection activities in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our recent studies provide evidence for involvement of RFGs mediated mechanisms in neuroprotection as revealed by reduced demyelination (loss of both myelin proteins and lipids) and loss of OL-progenitors in EAE. Moreover, in vitro studies with mixed glial cultures document that RFGs mediated mechanisms may also potentially provide promyelinating effects as evidenced by enhanced survival and differentiation of oligodendrocyte (OL)-progenitors. Importantly, these effects of statins were attributed to be the specific depletion of intracellular isoprenoids rather than the level of cholesterol in the cells or CNS. Moreover, the observed reduced levels of peroxisome proliferator activated receptors (PPARs) in the CNS of EAE and their normalization and activation by statin indicates that statin-RFGs mediated mechanisms may regulate the cellular homeostasis of PPARs. Based on this information, we hypothesize that statin mediated regulation of RFGs may modulate PPARs activities in OL-progenitors to promote their differentiation into remyelinating OLs in the CNS of EAE animals. The following studies are proposed to test this hypothesis. Specific aim 1: To investigate the RFGs mediated regulatory mechanisms for PPARs activation for the survival and differentiation of OL-progenitors in vitro cell culture systems. Specific aim 2: To evaluate the significance of RFGs induced PPARs activities in the induction of myelin repair in the inflammatory demyelinating model of EAE. The novelty of the study is to identify new therapeutic targets for induction of myelin repair for improved treatment and management of neurodegenerative diseases such as MS. Therapeutic targeting of neural cell mechanisms in inflammatory demyelinating model is essentially an innovative approach. PUBLIC HEALTH RELEVANCE: MS an autoimmune inflammatory demyelinating disease, affects approximately 400,000 individuals in US only and over 2.0 million individuals worldwide. In spite of the current therapeutics targeting immune response, the disease often progresses leading to neurodegeneration and thus physical disability reflecting the CNS injury. Therefore, the lack of effective treatments for MS represents a significant gap for treating the CNS disease. In addition to the anti-inflammatory and immunomodulatory properties the recently observed neuroprotective activities of statins identify novel aspect of their mechanisms for myelin repair by targeting the endogenous precursor cell. The proposed studies are innovative as they will improve our understanding of mechanisms for pharmacological enhancement of the potential of CNS endogenous cells to treat CNS disease (myelin repair) in MS. These studies will identify therapeutic targets for induction of myelin repair in MS and these findings should be applicable to other related neurodegenerative diseases.